The long-term objective of this application is to understand the mechanisms that control the growth and maintenance, differentiation, and migration of neural progenitor cells in the mammalian cerebral cortex. During development, neurons of the cerebral cortex arise from neural progenitor cells in the neuroepithelium, also called the ventricular zone. Neural progenitor cells initially grow within the ventricular zone. As corticogenesis proceeds, they differentiate into neurons, which migrate out of the ventricular zone into their final residence in the cortical plate. How the decision of growth vs. differentiation is made during this developmental progression of corticogenesis is largely unknown. Our preliminary studies identified the ephrin-B reverse signaling pathway as a candidate system in regulation of this choice point. Ephrin-B is the transmembrane ligand of the Eph receptor tyrosine kinases. Ephrins and Ephs are distinctive in that they mediate bi-directional signaling in many cell-cell interactions-a typical forward signal by Ephs and a unique reverse signal through ephrins. In the developing mouse cerebral cortex, ephrin-B1 and its downstream signaling effector protein PDS-RGS3 are specifically co-expressed in neural progenitor cells. Blocking ephrin-B1 expression results in outward migration of the affected neural progenitor cells into the cortical plate, most likely as a result of differentiation. The current study will further investigate this novel mechanism of control in neural progenitor cells. The specific aims include: (1) characterize the temporal and spatial expression patterns of ephrin-Bs and their cognate EphB receptors in relation to neural progenitor cells in the mouse cerebral cortex; (2) define the role of ephrin-B1 in growth vs. differentiation, and determine the contribution of the reverse signaling pathway in this function of ephrin-B1; and (3) investigate the mechanisms that control the expression of ephrin-B1 in neural progenitor cells. These studies are expected to contribute to our understanding on the development of the cerebral cortex and should help in improving the effectiveness of using neural progenitor/stem cells in cell replacement therapy.